Heterosubstituted N-thiolated beta-lactam compounds and methods of use

ABSTRACT

The invention relates to heterosubstituted N-thiolated beta-lactams, compositions comprising these compounds, methods for their production, and methods of use as antibiotics to inhibit the growth of bacteria. In one embodiment, the compounds have the structure shown in formula (A) or formula (B) or formula (C): 
                         
wherein the R groups are as defined in the specification. The antibacterial agents of the invention can be administered to a human or animal to treat or inhibit bacterial infection, such as that of  Staphylococcus  species, including methicillin-resistant  Staphylococcus aureus  (MRSA).

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. application Ser. No.11/852,100, filed Sep. 7, 2007, which claims the benefit of U.S.Provisional Application Ser. No. 60/844,291, filed Sep. 13, 2006, eachof which is hereby incorporated by reference herein in its entirety,including any figures, tables, nucleic acid sequences, amino acidsequences, and drawings.

GOVERNMENT SUPPORT

This invention was made with government support under grant number RO1AI051351 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

BACKGROUND OF THE INVENTION

For more than 60 years, N-thiolated β-lactam antibiotics have played anessential role in treating bacterial infections (Morin et al., 1982 andKukacs et al., 1990). The development of multi-drug resistantStaphylococcus infections is an increasing concern for the global healthcommunity. Infection caused by methicillin-resistant Staphylococcusaureus (MRSA) is becoming increasingly difficult to treat withconventional antibiotics, leading to a sharp rise in clinicalcomplications. Recently a new class of N-thiolated β-lactam has beenfound to inhibit bacterial growth in Staphylococcus aureus (Turos etal., 2000) including methicillin-resistant Staphylococcus aureus (MRSA)strains.

BRIEF SUMMARY OF THE INVENTION

The present invention concerns heterosubstituted N-thiolated beta-lactamcompounds, compositions comprising these compounds, methods for theirproduction, and methods of use as antibiotics to inhibit the growth ofbacteria. The antibacterial agents of the invention can be administeredto a human or animal to treat or inhibit bacterial infection(therapeutically or prophylactically), such as that of Staphylococcusspecies, including methicillin-resistant S. aureus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a reaction scheme for the synthesis of beta-lactams thatcan be used according to the present invention (see Turos et al.(2005)).

FIG. 2 shows a reaction scheme for the synthesis of a phthalimide dimerthat can be used according to the present invention (see Kalnins(1966)).

FIGS. 3A-3C show reaction schemes for the synthesis of heterosubstitutedN-thiolated beta-lactam compounds of the present invention.

FIGS. 4A-4C show examples of heterosubstituted N-thiolated beta-lactamcompounds of the present invention identified as compounds. FIG. 4A isstructure X, FIG. 4B is structure Y, and FIG. 4C is structure Z.

FIG. 5 shows bioactivity of heterosubstituted N-thiolated beta-lactamcompounds X, Y, and Z (shown in FIG. 4) of the present invention astested in Kirby-Bauer diffusion assay against methicillin resistantStaphylococcus aureus.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns heterosubstituted N-thiolatedbeta-lactams. In one embodiment, a beta-lactam compound of the inventionhas the structure shown in formula (A):

wherein R₁ is a hydrocarbon group having 1 to 8 carbon atoms and can be,for example, an alkyl, alkenyl, or alkynyl group;

R₃ is a heteroalkyl, heterocycloalkyl or heteroaryl, any of which can beoptionally substituted with R₂, wherein R₂ is one or more halides,hydroxyl, nitro, cyano, alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkoxy,amido, amino, carboxylic ester group, —CHO, —COOH, or COX, wherein X isCl, F, Br, or I;

R₄, R₅, and R₆ are, independently, hydrogen, alkyl, alkenyl, alkynyl,aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, halides, hydroxyl, nitro, cyano,alkoxy, amido, amino, carboxylic ester group, —CHO, —COOH, or COX,wherein X is Cl, F, Br, or I; any of which can be optionally substitutedwith R₂, wherein R₂ is one or more halides, hydroxyl, nitro, cyano,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, alkoxy, amido, amino, carboxylic estergroup, —CHO, —COOH, or COX, wherein X is Cl, F, Br, or I; and

wherein n=0 or 1;

or a pharmaceutically acceptable salt, hydrate, ester or amide thereof.

In one embodiment, a compound of the invention has the structure shownin formula (A) wherein R₁ is an alkyl group. In another embodiment, R₄is an aryl group. In a specific embodiment, R₁ is an alkyl group and R₄is an aryl group. In an exemplified embodiment, R₁ is a methyl and R₄ isphenyl optionally substituted with one or more halogens. In a specificembodiment, the halogen is Cl or Br. In a specific embodiment, R₃ isattached to the sulfur atom through a heteroatom, such as an N atom. Inone embodiment, R₃ is an optionally substituted phthalimido. In oneembodiment, a compound has the structure:

In an exemplified embodiment, a compound of the invention has thestructure shown below:

In another embodiment, a beta-lactam compound of the invention has thestructure shown in formula (B):

wherein R₁ is, independently, a hydrocarbon group having 1 to 8 carbonatoms and can be, for example, an alkyl, alkenyl, or alkynyl group; and

R₄, R₅, R₆, R₇, and R₈ are, independently, hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, halides, hydroxyl, nitro, cyano,alkoxy, amido, amino, carboxylic ester group, —CHO, —COOH, or COX,wherein X is Cl, F, Br, or I, any of which can be optionally substitutedwith R₂, wherein R₂ is one or more halides, hydroxyl, nitro, cyano,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, alkoxy, amido, amino, carboxylic estergroup, —CHO, —COON, or COX, wherein X is F, Br, or I;

wherein n=0 or 1;

or a pharmaceutically acceptable salt, hydrate, ester or amide thereof.

In one embodiment, a compound of the invention has the structure shownin formula (B) wherein R₁ is an alkyl group. In another embodiment, R₄is an aryl group. In a specific embodiment, R₁ is an alkyl group and R₄is an aryl group. In an exemplified embodiment, R₁ is a methyl and R₄ isphenyl optionally substituted with one or more halogens. In a specificembodiment, the halogen is Cl or Br. In one embodiment, a compound hasthe structure:

In an exemplified embodiment, a compound of the invention has thestructure shown below:

In another exemplified embodiment, a compound of the invention has thestructure shown below:

The subject invention also concerns prodrugs of the compounds describedherein. Prodrugs of compounds refers to compounds that can undergochemical changes when provided under physiological conditions, such aswhen the prodrug is administered to a person or animal, to therebyconvert the prodrug into an N-thiolated beta-lactam compound of thepresent invention.

The subject invention also concerns methods for synthesizing compoundsof the invention. General reaction schemes are shown below:

wherein R₁ is a hydrocarbon group having 1 to 8 carbon atoms and can be,for example, an alkyl, alkenyl, or alkynyl group;

R₃ is a heteroalkyl, heterocycloalkyl or heteroaryl, any of which can beoptionally substituted with R₂, wherein R₂ is one or more halides,hydroxyl, nitro, cyano, alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkoxy,amido, amino, carboxylic ester group, —CHO, —COOH, or COX, wherein X isCl, F, Br, or I; and

R₄, R₅, R₆, R₇, and R₈ are, independently, hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, halides, hydroxyl, nitro, cyano,alkoxy, amido, amino, carboxylic ester group, —CHO, —COOH, or COX,wherein X is Cl, F, Br, or I, any of which can be optionally substitutedwith R₂, wherein R₂ is one or more halides, hydroxyl, nitro, cyano,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, alkoxy, amido, amino, carboxylic estergroup, —CHO, —COOH, or COX, wherein X is Cl, F, Br, or I;

wherein n=0 or 1;

or a pharmaceutically acceptable salt, hydrate, ester or amide thereof.

Beta-lactam starting material can be synthesized as described in Turoset al. (2005). In one embodiment, a beta-lactam starting material isreacted with phthalimide dimer in a solvent, such as chloroform (CHCl₃),and triethylamine (Et₃N) under room temperature conditions or reflux(heat) conditions at elevated temperature. Phthalimide dimer can besynthesized as described in Kalnins (1966). Chemical reactions andproducts are shown in FIGS. 3A-3C. Methods of synthesis related toN-thiolated beta-lactam are also disclosed in U.S. Pat. Nos. 6,476,015and 6,946,458.

The subject invention also concerns methods of using one or morecompounds of the invention to treat or prevent a bacterial infection. Inone embodiment, a method of the invention comprises administering aneffective amount of one or more compounds of the invention to a personor animal in need of treatment. Optionally, the subject methods providefor screening of persons or animals to determine whether the person oranimal has a bacterial infection amenable to treatment by a compound ofthe present invention. Patients that can be treated according to thepresent invention, include, but are not limited to, humans and othermammals (such as primates (monkey, chimpanzee, ape, etc.) dog, cat, cow,pig, horse, etc.), or bird, reptile, etc. Compounds and pharmaceuticallyacceptable compositions administered to the person or animal via anysuitable route, including, for example, orally or parenterally, byintravenous, intramuscular, intraperitoneally, subcutaneous or topicalroutes, or via nasal or rectal administration. An ordinarily skilledclinician can readily assess the patient to determine optimal dosage,dosage form, and dosage schedule for the patient.

Bacterial infections that can be treated or prevented include, but arenot limited to, infections caused by gram-positive bacteria, such asBacillus spp., Listeria spp., Staphylococcus spp., Streptococcus spp.,Enterococcus spp., and Clostridium spp., and gram-negative bacteria,such as Escherichia spp., Salmonella spp., Pseudomonas spp., Heliobacterapp., Legionella spp., Moraxella spp., Neisseria spp., Hemophilus spp.,Klebsiella spp. and Enterobacter spp. Other bacteria that can beinhibited or killed by compounds of the invention include Shigella spp.,Acromonas spp., Vibrio spp., Bordatella spp., Brucella spp., Treponemaspp., Leptospira spp., Corynebacter spp., Micrococcus spp., Streptomycesspp., Nocardia spp., Actinomyces spp., Yersinia spp., Chlamydia spp.,Mycoplasma spp., Rickettsiae spp., Pasteurella spp., Spirillum spp., andMycobacterium spp. In one embodiment, a person or animal being treatedaccording to the methods herein is infected with methicillin-resistantStaphylococcus aureus. In one embodiment, a compound of the invention isprovided as a pharmaceutically acceptable composition that comprises,for example, a pharmaceutically acceptable carrier or excipient.

The bioactivity of these compounds has been tested by Kirby-Bauerdiffusion assay against methicillin resistant Staphylococcus aureus(MRSA) and were found to have anti-bacterial activity against the MRSAequal to that of Vancomycin. For example, the compounds of the inventioncan be administered to humans or animals to inhibit the growth ofbacteria, such as Staphylococcus, including MRSA. The mode of action ofthese compounds is believed to be similar to N-thiolated beta-lactamsand they may be formulated and used in a similar fashion (see U.S. Pat.No. 6,946,458 (Turos) and U.S. Pat. No. 6,476,015 (Turos et al.), whichare incorporated herein by reference in their entirety).

The subject invention also concerns methods for killing or inhibitingthe growth of a bacterial organism. In one embodiment, a bacterialorganism is contacted with one or more compounds of the presentinvention. Bacterial organisms contemplated within the scope of theinvention include gram-positive bacteria, such as Bacillus spp.,Listeria spp., Staphylococcus spp., Streptococcus spp., Enterococcusspp., and Clostridium spp., and gram-negative bacteria, such asEscherichia spp., Salmonella spp., Pseudomonas spp., Heliobacter app.,Legionella spp., Moraxella spp., Neisseria spp., Hemophilus spp.,Klebsiella spp. and Enterobacter spp. Other bacteria that can beinhibited or killed by compounds of the invention include Shigella ssp.,Acromonas spp., Vibrio spp., Bordatella spp., Brucella spp., Treponemaspp., Leptospira spp., Corynebacter spp., Micrococcus spp., Streptomycesspp., Nocardia spp., Actinomyces spp., Yersinia spp., Chlamydia spp.,Mycoplasma spp., Rickettsiae spp., Pasteurella spp., Spirillum spp., andMycobacterium spp. In an exemplified embodiment, the bacterial organismis a methicillin-resistant strain of Staphylococcus aureus.

The compounds and compositions of the invention can also be formulatedfor feeding livestock and the use thereof is contemplated by the presentinvention.

The invention further encompasses methods for inhibiting the growth ofbacteria by contacting the bacteria with an effective amount of thecompounds of the invention in vitro or in vivo, or by applying thecompound to a substrate (surface) likely to come in contact with thebacteria, such as a work surface, table, surgical instrument, implant orother device to be placed in or on the body (i.e., foreign object to beinserted into a subject, such as a stent, catheter, access port,intravenous delivery tube (Hickman), heart valve, dental implant,electro-mechanical device, prosthetic device, glucose sensor, orstabilizing device such as orthopedic nails and pins), eating or cookingutensil, etc. The subject invention also concerns substrates which havea compound of the invention attached or applied thereto.

As used herein, alkyl means straight or branched chain, saturated ormono- or polyunsaturated hydrocarbon groups having from 1 to 20 carbonatoms and C_(1-x) alkyl means straight or branched chain alkyl groupscontaining from one up to X carbon atoms. For example, C₁₋₆ alkyl meansstraight or branched chain alkyl groups containing from one up to 6carbon atoms. Alkoxy means an alkyl-O— group in which the alkyl group isas previously described. Cycloalkyl includes a nonaromatic monocyclic ormulticyclic ring system, including fused and spiro rings, of from aboutthree to about 10 carbon atoms. A cyclic alkyl may optionally bepartially unsaturated. Cycloalkoxy means a cycloalkyl-O-group in whichcycloalkyl is as defined herein. Aryl means an aromatic monocyclic ormulticyclic carbocyclic ring system, including fused and spiro rings,containing from about six to about 14 carbon atoms. Aryloxy means anaryl-O— group in which the aryl group is as described herein.Alkylcarbonyl means a RC(O)— group where R is an alkyl group aspreviously described. Alkoxycarbonyl means an ROC(O)— group where R isan alkyl group as previously described. Cycloalkylcarbonyl means anRC(O)— group where R is a cycloalkyl group as previously described.Cycloalkoxycarbonyl means an ROC(O)— group where R is a cycloalkyl groupas previously described.

Heteroalkyl means a straight or branched-chain having from one to 20carbon atoms and one or more heteroatoms selected from nitrogen, oxygen,sulfur, or silicon, wherein the nitrogen and sulfur atoms may optionallybe oxidized, i.e., in the form of an N-oxide or an S-oxide.Heterocycloalkyl means a monocyclic or multicyclic ring system (whichmay be saturated or partially unsaturated), including fused and Spirorings, of about five to about 14 elements wherein one or more of theelements in the ring system is an element other than carbon and isselected from nitrogen, oxygen, silicon, or sulfur atoms. Heteroarylmeans a five to about a 14-membered aromatic monocyclic or multicyclichydrocarbon ring system, including fused and spiro rings, in which oneor more of the elements in the ring system is an element other thancarbon and is selected from nitrogen, oxygen, silicon, or sulfur andwherein an N atom may be in the form of an N-oxide. Arylcarbonyl meansan aryl-CO— group in which the aryl group is as described herein.Heteroarylcarbonyl means a heteroaryl-CO— group in which the heteroarylgroup is as described herein and heterocycloalkylcarbonyl means aheterocycloalkyl-CO— group in which the heterocycloalkyl group is asdescribed herein. Aryloxycarbonyl means an ROC(O)— group where R is anaryl group as previously described. Heteroaryloxycarbonyl means anROC(O)— group where R is a heteroaryl group as previously described.Heterocycloalkoxy means a heterocycloalkyl-O— group in which theheterocycloalkyl group is as previously described.Heterocycloalkoxycarbonyl means an ROC(O)— group where R is aheterocycloalkyl group as previously described.

Examples of saturated alkyl groups include, but are not limited to,methyl, ethyl, N-propyl, isopropyl, N-butyl, tert-butyl, isobutyl,sec-butyl, N-pentyl, N-hexyl, N-heptyl, and N-octyl. An unsaturatedalkyl group is one having one or more double or triple bonds.Unsaturated alkyl groups include, for example, ethenyl, propenyl,butenyl, hexenyl, vinyl, 2-propynyl, 2-isopentenyl, 2-butadienyl,ethynyl, 1-propynyl, 3-propynyl, 3-butynyl, 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl,1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl,7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl,5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl; 1-undecenyl,2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl,7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl,2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl,7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, 11-dodecenyl,1-tridecenyl, 2-tridecenyl, 3-tridecenyl, 4-tridecenyl, 5-tridecenyl,6-tridecenyl, 7-tridecenyl, 8-tridecenyl, 9-tridecenyl, 10-tridecenyl,11-tridecenyl, 12-tridecenyl, 1-tetradecenyl, 2-tetradecenyl,3-tetradecenyl, 4-tetradecenyl, 5-tetradecenyl, 6-tetradecenyl,7-tetradecenyl, 8-tetradecenyl, 9-tetradecenyl, 10-tetradecenyl,11-tetradecenyl, 12-tetradecenyl, 13-tetradecenyl, 1-pentadecenyl,2-pentadecenyl, 3-pentadecenyl, 4-pentadecenyl, 5-pentadecenyl,6-pentadecenyl, 7-pentadecenyl, 8-pentadecenyl, 9-pentadecenyl,10-pentadecenyl, 11-pentadecenyl, 12-pentadecenyl, 13-pentadecenyl, and14-pentadecenyl. Cycloalkyl groups include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl,cycloheptyl, and cyclooctyl. Heterocycloalkyl groups include, forexample, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 3-morpholinyl,4-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,2-piperazinyl, 1,4-diazabicyclooctane, and succinimido. Aryl groupsinclude, for example, phenyl, indenyl, biphenyl, 1-naphthyl, 2-naphthyl,anthracenyl, and phenanthracenyl. Heteroaryl groups include, forexample, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, furyl, thienyl, imidazolyl,oxazolyl, thiazolyl, pyrazolyl, pyridyl, indolyl, quinolinyl,isoquinolinyl, benzoquinolinyl, carbazolyl, phthalimido, pyrimidinyl,terazolyl, and diazaphenanthrenyl. “Alkoxy” can include methoxy, ethoxy,propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy,hexoxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy,tridecyloxy, tetradecyloxy, or pentadecyloxy.

As used herein, halogen means the elements fluorine (F), chlorine (Cl),Bromine (Br), and iodine (I).

Compounds of the subject invention also include hydrates andphysiologically-acceptable salts of the subject compounds.Physiologically-acceptable salts includes salts of the compounds of theinvention which are prepared with acids or bases, depending on theparticular substituents found on the subject compounds described herein.Examples of physiologically-acceptable base addition salts includesodium, potassium, calcium, ammonium, or magnesium salt. Examples ofphysiologically-acceptable acid addition salts include hydrochloric,hydrobromic, nitric, phosphoric, carbonic, sulfuric, and organic acidslike acetic, propionic, benzoic, succinic, fumaric, mandelic, oxalic,citric, tartaric, maleic, and the like. Physiologically-acceptable saltsof compounds of the invention can be prepared using conventionaltechniques.

It will be appreciated by those skilled in the art that compounds of theinvention may contain one or more asymmetrically substituted carbonatoms which can give rise to stereoisomers. It is understood that theinvention extends to all such stereoisomers, including enantiomers, anddiastereoisomers and mixtures, including racemic mixtures thereof.

Compounds of the subject invention can be formulated according to knownmethods for preparing physiologically acceptable compositions.Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Remington's Pharmaceutical Science by F. W. Martin describesformulations which can be used in connection with the subject invention.In general, the compositions of the subject invention will be formulatedsuch that an effective amount of the compound is combined with asuitable carrier in order to facilitate effective administration of thecomposition. The compositions used in the present methods can also be ina variety of forms. These include, for example, solid, semi-solid, andliquid dosage forms, such as tablets, pills, powders, liquid solutionsor suspension, suppositories, injectable and infusible solutions, andsprays. The preferred form depends on the intended mode ofadministration and therapeutic application. The compositions alsopreferably include conventional physiologically-acceptable carriers anddiluents which are known to those skilled in the art. Examples ofcarriers or diluents for use with the subject compounds include water,saline, ethanol, dimethyl sulfoxide, glycerol, alumina, starch, andequivalent carriers and diluents. To provide for the administration ofsuch dosages for the desired therapeutic treatment, compositions of theinvention will advantageously comprise between about 0.1% and 99%, andespecially, 1 and 15% by weight of the total of one or more of thesubject compounds based on the weight of the total composition includingcarrier or diluent.

In addition, the compounds of the present invention that exhibitantibacterial activity may also be used as medicaments, and also assubstances for preserving inorganic and organic materials, especiallyorganic materials of all kinds, for example, polymers, lubricants,paints, fibers, leather, paper, timber, foodstuffs, and water. Forexample, these compounds can be covalently bonded to the polymer.

The subject invention also concerns a kit comprising in one or morecontainers at least one compound of the subject invention. In oneembodiment, a kit of the invention also comprises a pharmaceuticallyacceptable diluent and/or carrier. A kit of the invention can alsocomprise, in addition to at least one compound of the present invention,other antibiotics, such as penicillin, cephalosporins, carbapenems, andbeta-lactamase inhibitors.

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety, including all figures and tables, to the extent theyare not inconsistent with the explicit teachings of this specification.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication and the scope of the appended claims. In addition, anyelements or limitations of any invention or embodiment thereof disclosedherein can be combined with any and/or all other elements or limitations(individually or in any combination) or any other invention orembodiment thereof disclosed herein, and all such combinations arecontemplated with the scope of the invention without limitation thereto.

REFERENCES

-   U.S. Pat. No. 6,946,458-   U.S. Pat. No. 6,476,015-   Kalnins, Malda (1966) “Reactions of Phthalimide and Potassium    Phthalimide with Sulfur Monochloride,” Canadian Journal of    Chemistry, 44: 2111-2113.-   Morin et al. (1982) “Chemistry and Biology of beta-lactam    Antibiotics,” Vol. 1-3. New York: Academic Press.-   Kukacs et al. (1990) “Recent Progress in the Chemical Synthesis of    Antibiotics” Berlin, Springer-Verlag.-   Turos, E. et al. (2005) “N-Methylthio β-lactam Antibacterials:    Effects of the C₃/C₄ Ring Substituents on Anti-MRSA Activity,”    Bioorganic $ Medicinal Chemistry, 13: 6289-6308.-   Turos et al. (2000) Tetrahedron 56:5571-5578.-   Ren et al. (1998) J. Org. Chem. 63: 8898-8917.

We claim:
 1. A compound having the structure shown in formula (B):

wherein R₁ is a hydrocarbon group having 1 to 8 carbon atoms; andwherein R₄ , R₅, R₆, R₇, and R₈ are, independently, hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, hydroxyl,nitro, cyano, alkoxy, amido, amino, —CHO, —COOH, or COX, wherein X isCl, F, Br, or I, any of which can be optionally substituted with R₂,wherein R₂ is one or more halogen, hydroxyl, nitro, cyano, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, alkoxy, amido, amino, —CHO, —COOH, orCOX, wherein X is Cl, F, Br, or I; and wherein n=0 or 1; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R₁ is alkyl.
 3. The compound according to claim 1,wherein R₄ is aryl.
 4. The compound according to claim 1, wherein R₁ isalkyl and R₄ is aryl.
 5. The compound according to claim 1, wherein R₁is methyl and R₄ is phenyl optionally substituted with one or morehalogen.
 6. The compound according to claim 5, wherein said one or morehalogen are selected from the group consisting of Cl and Br.
 7. Acomposition comprising a compound having the structure shown in formula(B)

wherein R₁ is a hydrocarbon group having 1 to 8 carbon atoms; andwherein R₄, R₅, R₆, R₇, and R₈ are, independently, hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, hydroxyl,nitro, cyano, alkoxy, amido, amino, —CHO, —COOH, or COX, wherein X isCl, F, Br, or I, any of which can be optionally substituted with R₂,wherein R₂ is one or more halogen, hydroxyl, nitro, cyano, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, alkoxy, amido, amino, —CHO, —COOH, orCOX, wherein X is Cl, F, Br, or I; wherein n=0 or 1; or apharmaceutically acceptable salt, hydrate, ester or amide thereof; and apharmaceutically acceptable carrier, diluent, or excipient.
 8. A methodfor treating or preventing a bacterial infection in a person or animal,said method comprising administering an effective amount of a compound,or a composition comprising said compound, to said person or animal,wherein said compound has the structure shown in formula (B):

wherein R₁ is a hydrocarbon group having 1 to 8 carbon atoms; andwherein R₄, R₅, R₆, R₇, and R₈ are, independently, hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl,heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, halogen, hydroxyl,nitro, cyano, alkoxy, amido, amino, —CHO, —COOH, or COX, wherein X isCl, F, Br, or I, any of which can be optionally substituted with R₂,wherein R₂ is one or more halogen, hydroxyl, nitro, cyano, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, alkoxy, amido, amino, —CHO, —COOH, orCOX, wherein X is Cl, F, Br, or I; and wherein n=0 or 1; or apharmaceutically acceptable salt, hydrate, ester or amide thereof. 9.The method according to claim 8, wherein R₁ is alkyl.
 10. The methodaccording to claim 8, wherein R₄ is aryl.
 11. The method according toclaim 8, wherein R₁ is alkyl and R₄ is aryl.
 12. The method according toclaim 8, wherein R₁ is methyl and R₄ is phenyl optionally substitutedwith one or more halogen.
 13. The method according to claim 12, whereinsaid one or more halogen are selected from the group consisting of Cland Br.
 14. The method according to claim 8, wherein the compound hasthe structure:

or a pharmaceutically acceptable salt or hydrate thereof.
 15. The methodaccording to claim 8, wherein the compound has the structure:

or a pharmaceutically acceptable salt or hydrate thereof.
 16. The methodaccording to claim 8, wherein said animal is a primate, dog, cat, cow,pig, or horse.
 17. The method according to claim 8, wherein saidbacterial infection is caused by one of the following bacteria: Bacillusspp., Listeria spp., Staphylococcus spp., Streptococcus spp.,Enterococcus spp., Clostridium spp., Escherichia spp., Salmonella spp.,Pseudomonas spp., Heliobacter spp., Legionella spp., Moraxella spp.,Neisseria spp., Hemophilus spp., Klebsiella spp., Enterobacter spp.,Shigella spp., Acromonas spp., Vibrio spp., Bordatella spp., Brucellaspp., Treponema spp., Leptospira spp., Corynebacter spp., Micrococcusspp., Streptomyces spp., Nocardia spp., Actinomyces spp., Yersinia spp.,Chlamydia spp., Mycoplasma spp., Rickettsiae spp., Pasteurella spp.,Spirillum spp., or Mycobacterium spp.
 18. The method according to claim8, wherein said bacterial infection is caused by a methicillin resistantstrain of Staphylococcus aureus.
 19. The method according to claim 8,wherein said compound or composition is administered to said person oranimal via an oral, parenteral, nasal, or rectal route ofadministration.
 20. The method according to claim 8, wherein saidcomposition comprises a pharmaceutically acceptable carrier, diluent, orexcipient.
 21. A method for treating or preventing a bacterial infectionin a person or animal, said method comprising administering an effectiveamount of a compound, or a composition comprising said compound, to saidperson or animal, wherein said compound has the structure shown informula (A):

wherein R₁ is a hydrocarbon group having 1 to 8 carbon atoms; R₄, R₅,and R₆ are, independently, hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, halogen, hydroxyl, nitro, cyano, alkoxy, amido,amino, —CHO, —COOH, or COX, wherein X is Cl, F, Br, or I; any of whichcan be optionally substituted with R₂, wherein R₂ is one or morehalogen, hydroxyl, nitro, cyano, alkyl, alkenyl, alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl,heterocycloalkenyl, alkoxy, amido, amino, —CHO, —COOH, or COX, wherein Xis Cl, F, Br, or I; and wherein n=0 or 1; or a pharmaceuticallyacceptable salt, hydrate, ester or amide thereof.
 22. The methodaccording to claim 21, wherein R₁ is alkyl.
 23. The method according toclaim 21, wherein R₄ is aryl.
 24. The method according to claim 21,wherein R₁ is alkyl and R₄ is aryl.
 25. The method according to claim21, wherein R₁ is methyl and R₄ is phenyl optionally substituted withone or more halogen.
 26. The method according to claim 25, wherein saidone or more are selected from the group consisting of Cl and Br.
 27. Themethod according to claim 21, wherein the compound has the structure:

or a pharmaceutically acceptable salt or hydrate thereof.
 28. The methodaccording to claim 21, wherein said animal is a primate, dog, cat, cow,pig, or horse.
 29. The method according to claim 21, wherein saidbacterial infection is caused by one of the following bacteria: Bacillusspp., Listeria spp., Staphylococcus spp., Streptococcus spp.,Enterococcus spp., Clostridium spp., Escherichia spp., Salmonella spp.,Pseudomonas spp., Heliobacter spp., Legionella spp., Moraxella spp.,Neisseria spp., Hemophilus spp., Klebsiella spp., Enterobacter spp.,Shigella spp., Aeromonas spp., Vibrio spp., Bordatella spp., Brucellaspp., Treponema spp., Leptospira spp., Corynebacter spp., Micrococcusspp., Streptomyces spp., Nocardia spp., Actinomyces spp., Yersinia spp.,Chlamydia spp., Mycoplasma spp., Rickettsiae spp., Pasteurella spp.,Spirillum spp., or Mycobacterium spp.
 30. The method according to claim21, wherein said bacterial infection is caused by a methicillinresistant strain of Staphylococcus aureus.
 31. The method according toclaim 21, wherein said compound or composition is administered to saidperson or animal via an oral, parenteral, nasal, or rectal route ofadministration.
 32. The method according to claim 21, wherein saidcomposition comprises a pharmaceutically acceptable carrier, diluent, orexcipient.
 33. A method for treating or preventing a bacterial infectionin a person or animal, said method comprising administering an effectiveamount of a compound, or a composition comprising said compound, to saidperson or animal, wherein said compound has the structure shown informula (C):

wherein R₂ is one or more halogen, hydroxyl, nitro, cyano, alkyl,alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, alkoxy, amino, amino, —CHO, —COON, orCOX, wherein X is Cl, F, Br, or I; or a pharmaceutically acceptable saltor hydrate thereof.
 34. The method according to claim 33, wherein R₂ isone or more halogen.
 35. The method according to claim 34, wherein saidone or more halogen is selected from the group consisting of Cl and Br.36. The method according to claim 33, wherein said animal is a primate,dog, cat, cow, pig, or horse.
 37. The method according to claim 33,wherein said bacterial infection is caused by one of the followingbacteria: Bacillus spp., Listeria spp., Staphylococcus spp.,Streptococcus spp., Enterococcus spp., Clostridium spp., Escherichiaspp., Salmonella spp., Pseudomonas spp., Heliobacter spp., Legionellaspp., Moraxella spp., Neisseria spp., Hemophilus spp., Klebsiella spp.,Enterobacter spp., Shigella spp., Aeromonas spp., Vibrio spp.,Bordatella spp., Brucella spp., Treponema spp., Leptospira spp.,Corynebacter spp., Micrococcus spp., Streptomyces spp., Nocardia spp.,Actinomyces spp., Yersinia spp., Chlamydia spp., Mycoplasma spp.,Rickettsiae spp., Pasteurella spp., Spirillum spp., or Mycobacteriumspp.
 38. The method according to claim 33, wherein said bacterialinfection is caused by a methicillin resistant strain of Staphylococcusaureus.
 39. The method according to claim 33, wherein said compound orcomposition is administered to said person or animal via an oral,parenteral, nasal, or rectal route of administration.
 40. The methodaccording to claim 33, wherein said composition comprises apharmaceutically acceptable carrier, diluent, or excipient.
 41. Thecompound of claim 1, wherein the salt is a sodium, potassium, calcium,ammonium, magnesium, hydrochloric, hydrobromic, nitric, phosphoric,carbonic, sulfuric, acetic acid, propionic acid, benzoic acid, succinicacid, fumaric acid, mandelic acid, oxalic acid, citric acid, tartaricacid, or maleic acid salt.
 42. The composition of claim 7, wherein thesalt is a sodium, potassium, calcium, ammonium, magnesium, hydrochloric,hydrobromic, nitric, phosphoric, carbonic, sulfuric, acetic acid,propionic acid, benzoic acid, succinic acid, fumaric acid, mandelicacid, oxalic acid, citric acid, tartaric acid, or maleic acid salt. 43.The method of claim 8, wherein the salt is a sodium, potassium, calcium,ammonium, magnesium, hydrochloric, hydrobromic, nitric, phosphoric,carbonic, sulfuric, acetic acid, propionic acid, benzoic acid, succinicacid, fumaric acid, mandelic acid, oxalic acid, citric acid, tartaricacid, or maleic acid salt.
 44. The method of claim 21, wherein the saltis a sodium, potassium, calcium, ammonium, magnesium, hydrochloric,hydrobromic, nitric, phosphoric, carbonic, sulfuric, acetic acid,propionic acid, benzoic acid, succinic acid, fumaric acid, mandelicacid, oxalic acid, citric acid, tartaric acid, or maleic acid salt. 45.The method of claim 33, wherein the salt is a sodium, potassium,calcium, ammonium, magnesium, hydrochloric, hydrobromic, nitric,phosphoric, carbonic, sulfuric, acetic acid, propionic acid, benzoicacid, succinic acid, fumaric acid, mandelic acid, oxalic acid, citricacid, tartaric acid, or maleic acid salt.